Glutathione in Diabetic Nephropathy (CGDN)

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Department of Veterans Affairs
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Department of Veterans Affairs
ClinicalTrials.gov Identifier:
NCT01265563
First received: December 10, 2010
Last updated: May 12, 2014
Last verified: May 2014
  Purpose

The study is done to find out whether the combined use of the nutritional supplements N-acetylcysteine and Siliphos (milk thistle extract) corrects the shedding of urine protein and oxidative damage (damage to cells and organs often compared to fast aging) in patients with Type 2 Diabetes Mellitus (T2DM) and diabetic kidney disease.


Condition Intervention Phase
Diabetic Nephropathy
Proteinuria
Oxidative Stress
Drug: N-acetylcysteine placebo + silibin placebo
Drug: N-acetylcysteine active + silibin placebo
Drug: N-acetylcysteine placebo + silibin active
Drug: N-acetylcysteine active + silibin active
Drug: N-acetylcysteine active + high-dose silibin active
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Correction of Glutathione Deficiency for Treatment of Diabetic Nephropathy

Resource links provided by NLM:


Further study details as provided by Department of Veterans Affairs:

Primary Outcome Measures:
  • Change from baseline in urinary albumin excretion [ Time Frame: 3-month ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Change from baseline in urinary alpha-1 microglobulin excretion [ Time Frame: 3-month ] [ Designated as safety issue: No ]
  • Change from baseline in urinary C-C-chemokines excretion [ Time Frame: 3-month ] [ Designated as safety issue: No ]
  • Change from baseline in peripheral blood monocyte glutathione content [ Time Frame: 3-month ] [ Designated as safety issue: No ]
  • adverse events [ Time Frame: 1-month ] [ Designated as safety issue: Yes ]
  • Change from baseline in hemoglobin level [ Time Frame: 1-month ] [ Designated as safety issue: Yes ]
  • Change from baseline in serum electrolytes [ Time Frame: 1-month ] [ Designated as safety issue: Yes ]
  • Change from baseline in estimated glomerular filtration rate [ Time Frame: 1-month ] [ Designated as safety issue: Yes ]
  • Change from baseline in measured glomerular filtration rate [ Time Frame: 3-month ] [ Designated as safety issue: Yes ]
  • Change from baseline in hemoglobin-A1c [ Time Frame: 1-month ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 110
Study Start Date: January 2011
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Arm 1
N-acetylcysteine placebo + silibin placebo Dietary Supplement: N-acetylcysteine placebo excipient orally twice daily for three months Other Name: NAC placebo Dietary Supplement: silibin placebo excipient orally twice daily for three months Other Name: silibin-phosphatidylcholine placebo, Siliphos placebo
Drug: N-acetylcysteine placebo + silibin placebo
Dietary Supplement: N-acetylcysteine placebo excipient orally twice daily for three months
Other Name: NAC placebo Dietary Supplement: silibin placebo excipient orally twice daily for three months Or silibin-phosphatidylcholine placebo, Siliphos placebo
Experimental: Arm 2
N-acetylcysteine active + silibin placebo Dietary Supplement: N-acetylcysteine 600 mg orally twice daily for three months Other Name: NAC Dietary Supplement: silibin placebo excipient orally twice daily for three months Other Name: silibin-phosphatidylcholine placebo, Siliphos placebo
Drug: N-acetylcysteine active + silibin placebo
Dietary Supplement: N-acetylcysteine 600 mg orally twice daily for three months
Other Name: NAC Dietary Supplement: silibin placebo excipient orally twice daily for three months Or Silibin-phosphatidylcholine placebo, Siliphos placebo
Experimental: Arm 3
N-acetylcysteine placebo + silibin active Dietary Supplement: silibin 480 mg orally twice daily for three months Other Name: silibin-phosphatidylcholine, Siliphos Dietary Supplement: N-acetylcysteine placebo excipient orally twice daily for three months Other Name: NAC placebo Dietary Supplement: silibin placebo excipient orally twice daily for three months Other Name: silibin-phosphatidylcholine placebo, Siliphos placebo
Drug: N-acetylcysteine placebo + silibin active

Dietary Supplement: silibin 480 mg orally twice daily for three months

  • (Other Name) Silibin-phosphatidylcholine placebo, Siliphos placebo
  • (Other Name) NAC placebo Dietary Supplement: silibin placebo excipient orally twice daily for three months
Other Name: Silibin-phosphatidylcholine, Siliphos Dietary Supplement: N-acetylcysteine placebo excipient orally twice daily for three months
Experimental: Arm 4
N-acetylcysteine active + silibin active Dietary Supplement: N-acetylcysteine 600 mg orally twice daily for three months Other Name: NAC Dietary Supplement: silibin 480 mg orally twice daily for three months Other Name: silibin-phosphatidylcholine, Siliphos Dietary Supplement: silibin placebo excipient orally twice daily for three months Other Name: silibin-phosphatidylcholine placebo, Siliphos placebo
Drug: N-acetylcysteine active + silibin active

Dietary Supplement: N-acetylcysteine 600 mg orally twice daily for three months

  • (Other Name): NAC Dietary Supplement: silibin 480 mg orally twice daily for three months Silibin-phosphatidylcholine, Siliphos Dietary Supplement: silibin placebo excipient orally twice daily for three months
  • (Other Name): Silibin-phosphatidylcholine, Siliphos Dietary Supplement: silibin placebo excipient orally twice daily for three months
Other Name: Silibin-phosphatidylcholine placebo, Siliphos placebo
Experimental: Arm 5
N-acetylcysteine active + high-dose silibin active Dietary Supplement: N-acetylcysteine 600 mg orally twice daily for three months Other Name: NAC Dietary Supplement: high-dose silibin 960 mg orally twice daily for three months Other Name: silibin-phosphatidylcholine, Siliphos
Drug: N-acetylcysteine active + high-dose silibin active
Dietary Supplement: N-acetylcysteine 600 mg orally twice daily for three months
Other Name: NAC Dietary Supplement: high-dose silibin 960 mg orally twice daily for three months Or Other Name: Silibin-phosphatidylcholine, Siliphos

Detailed Description:

Oxidative stress and glutathione (GSH) imbalance are major contributors to the pathogenesis of diabetic nephropathy. Current options for the treatment of oxidative stress in diabetic nephropathy are limited and only partially effective, thus interest in the development of new strategies is high.

The study intends to test the hypothesis that combined oral supplementation of the antioxidants N-acetylcysteine (NAC) and milk thistle flavonolignan silibin (as silibin-phosphatidylcholine) will reduce proteinuria and urinary and systemic manifestations of oxidative stress and inflammation, which are characteristically observed in patients with T2DM and related nephropathy. We expect these effects to be achieved with minimal or no side effects, and with good patient tolerance.

The trial is designed as a two-center, double-blind, placebo-controlled, randomized, modified-factorial dose-ranging design, five-arm pilot study in patients with Type 2 diabetes mellitus and advanced diabetic nephropathy with proteinuria.

Intervention consists of three-month oral administration of NAC, silibin, and/or respective placebos for three months. Subjects are randomized to the following five intervention arms: (A) placebo; (B) NAC; (C) silibin; (D) NAC + silibin; and (E) NAC + double-dose silibin.

The primary outcome measure is urinary excretion of albumin, a marker of glomerular injury. Secondary outcome measures are alpha-1 microglobulin, a marker of tubular injury, and urinary excretion of inflammatory cytokines and C-C chemokines, i.e. markers of renal inflammation. In addition, peripheral blood monocytes from the same patients are analyzed for GSH content and activity of GSH metabolizing enzymes. All outcome measures are monitored in relation to both treatment allocation and prevalent blood and urine levels of the active treatment. Safety and tolerability of this combination treatment are monitored throughout the trial.

  Eligibility

Ages Eligible for Study:   18 Years to 76 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Males or females age 18-76 years old
  • Type 2 diabetes mellitus
  • Diabetic nephropathy, as defined by:

    • estimated GFR between 60 and 15 ml/min
    • presence of proteinuria
  • Current medical treatment with low dose aspirin
  • Treatment of hypertension with (but not limited to):

    • one diuretic
    • one beta-blocker
    • and one medication from the classes Angiotensin Receptor Blockers (ARBs) or Angiotensin Converting Enzyme inhibitors (ACE-I)
  • Treatment of hyperglycemia with (but not limited to) glipizide and the medication class insulin
  • Treatment of hypercholesterolemia with (but not limited to) one medication from the class statins

Exclusion Criteria:

  • Type 1 diabetes mellitus
  • Glycosylated hemoglobin (HbA1C) > 10%
  • >20% variation in estimated GFR, during last 6 months
  • Systolic Blood Pressure >170 mmHg or Diastolic Blood Pressure >100 mmHg on medications
  • Other secondary forms of hypertension (endocrine, renovascular)
  • History of intolerance to:

    • Both ACE-I and ARBs
    • The investigational supplements
    • Iodinated radiologic contrast material
  • Known non diabetic renal disease
  • or history of solid organ transplantation
  • Hepatitis virus or Human Immunodeficiency virus infections
  • Use of one of the following medications within 2 months prior to enrollment in the study:

    • Metformin
    • Thiazolidinediones (pioglitazone or rosiglitazone)
    • Phenytoin
    • Warfarin
    • Prescription-grade vitamin E, vitamin C, systemic steroids, and/or non-steroidal anti-inflammatory agents
    • Over-the-counter vitamin E, vitamin C, and/or non-steroidal anti-inflammatory agents
    • Over-the-counter antioxidants supplements including:

      • Lipoic acid
      • Coenzyme Q10
      • N-acetyl-cysteine (NAC)
      • Glutathione (GSH)
      • Chromium
      • Fish-oil extracts (omega-3 fatty acids)
      • Soy extracts (isoflavones)
      • Milk thistle extract (silymarin)
      • Green-tea preparations
      • Pomegranate extracts
      • Grape extracts
      • Prickly pear extract
  • Active coronary artery disease or cerebral vascular disease within 3 months prior to signing the informed consent
  • Hepatic dysfunction as defined by abnormal total bilirubin or liver enzymes (ALT, AST) >2 times upper limit of normal range
  • Active malignancy
  • History of drug or alcohol dependency
  • Psychiatric or neurological condition, preventing aware consent to the study and/or adherence to the study protocol
  • Unwillingness to practice birth control throughout the study
  • Participation to another clinical study within 1 month prior to signing the informed consent form
  • Planned move to outside the study area, surgery or radiographic studies utilizing iodine-based contrast material within the next one year
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01265563

Contacts
Contact: Lih-Lan Hu, MPH (210) 567-5882 hus@livemail.uthscsa.edu
Contact: Sue Cunningham, PhD (210) 567-8836 cunninghams@uthscsa.edu

Locations
United States, Texas
VA South Texas Health Care System, San Antonio Recruiting
San Antonio, Texas, United States, 78229
Contact: Lih-Lan Hu, MPH    210-567-5882    hus@livemail.uthscsa.edu   
Contact: Sue Cunningham, PhD    (210) 567-8836    cunninghams@uthscsa.edu   
Principal Investigator: Paolo Fanti, MD         
Sponsors and Collaborators
Investigators
Principal Investigator: Paolo Fanti, MD VA South Texas Health Care System, San Antonio
  More Information

Publications:
Responsible Party: Department of Veterans Affairs
ClinicalTrials.gov Identifier: NCT01265563     History of Changes
Other Study ID Numbers: CLIN-004-10S, 1R21AT004490-01A1, VA 1I01CX000264-01A2
Study First Received: December 10, 2010
Last Updated: May 12, 2014
Health Authority: United States: Federal Government

Keywords provided by Department of Veterans Affairs:
silymarin
glutathione
diabetic nephropathies
oxidative stress

Additional relevant MeSH terms:
Antioxidants
Diabetic Nephropathies
Kidney Diseases
Proteinuria
Urologic Diseases
Diabetes Complications
Diabetes Mellitus
Endocrine System Diseases
Urination Disorders
Urological Manifestations
Signs and Symptoms
Acetylcysteine
N-monoacetylcystine
Silybin
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Expectorants
Respiratory System Agents
Free Radical Scavengers
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Antidotes

ClinicalTrials.gov processed this record on July 24, 2014